Project 1 Summary EFFECTS OF CHRONIC DRUG COMBINATION TREATMENTS ON THE REINFORCING AND COGNITIVE EFFECTS OF COCAINE IN RODENTS AND MONKEYS Michael A. Nader, PI Paul W. Czoty, Thomas J. Martin, Mark J. Ferris, Mei-Chuan Ko, Daniel Yohannes, Co-Is The goal of this Project is to achieve a better understanding of the pharmacological determinants of the reinforcing effects of cocaine in rodent and nonhuman primate models of drug abuse. In the previous funding period, we found that monoamine releasers d-amphetamine, phenmetrazine (PM) and phendimetrazine (PDM) effectively decreased cocaine self-administration in rats and monkeys. For the studies proposed in Project 1, we will incorporate a strategy that involves drug combinations in order to meet two goals: (1) reduce the amount of drug (i.e., PM or PDM) necessary to decrease cocaine self-administration and (2) improve treatment efficacy. For all studies, one of the drugs (Drug A) will be PM (in rats) and PDM (in monkeys). The combination drug (Drug B) will be based on input from our clinicial colloborators and be a compound that improves cognitive performance in animals with a cocaine history. In Specific Aim 1, rats will self-administer cocaine under a long-access 6-hr session; some rats will then be tested in two paradigms designed to assess cognition/attention/impulsivity, the delayed discounting procedure and the 5-choice serial reaction time task. Drug B candidates that show remediation of cocaine-induced disruptions in cognitive performance will be tested in another group of rats self-administering cocaine and co-treated with PM. Drug B candidates that effectively reduce rodent self-administration will be tested in nonhuman primates (Specific Aim 2) under two different cocaine access conditions - progressive-ratio and concurrent food-cocaine choice. If the combination of PDM and Drug B effectively decreases cocaine self-administration under either condition, the effects of the combination on cognitive performance and physiology, as assessed with telemetry, will be examined in these same monkeys (Specific Aim 3). These studies combine chronic drug treatment and drug combinations under multiple behavioral conditions in rats and monkeys and should provide valuable translational information for the development of novel cocaine pharmacotherapies.